Genome instability is generally deleterious to cell growth. Paradoxically, in cancer, it is associated with increased
drug resistance, metastasis and immune evasion; all of which contribute to poor patient prognosis. The broader
landscape of our research is to fully understand how the DNA damage response (DDR) pathway and mitotic
machinery work in concert to promote faithful genome stability. A major component of the DDR pathway is Ataxia
telangiectasia and Rad3 related (ATR) kinase. I previously discovered an unexpected, and novel DNA damage-
independent, role for ATR kinase after mitotic entry. This newly revealed role for ATR is essential for genome
stability. This unexpected role for ATR opened up many opportunities to understand cross-talk between the
pathways that regulate genomic stability and is foundational to my lab.
Our long-term goal is to make unique contributions by elucidating how the non-canonical roles of the proteins
that make up the DDR pathway ensure genome stability. Our five-year goal is to further our understanding of the
mechanisms by which ATR promotes genome stability outside of the DNA damage response pathway in both
mitosis (program 1) and interphase (program 2).
Our current understanding of the mitotic function of ATR is limited to our previous observations that ATR activates
promotes proper Aurora B activity. This leaves a large gap of knowledge as to how ATR promotes proper
chromosome segregation. We will explore the mitotic pathways that ATR regulates, focusing on putative direct
substrates that we have identified (program 1).
Additionally, our previous work uncovered two novel, DDR independent functions of ATR, which we aim to fully
explore in this proposal (program 2). (1) ATR directly phosphorylates lamin A/C in interphase. This has prompted
us to define the function of ATR on nuclear plasticity and nuclear envelope breakdown. (2) Basal ATR activity is
necessary for proper centromere identity throughout interphase. We will focus on how basal ATR activity
promotes proper centromere identity and function through its regulation of promyelocytic nuclear bodies.
We expect that these projects will yield critical information on the role of ATR in mitosis and how it and the DNA
damage response pathway promote faithful chromosome segregation independent of DNA damage and further
our understanding of the mechanism that promote genome stability.